In animals, the recreational drug 3,4-methylenedioxymethamphetamine (MDMA) is a documented serotonin (5-HT) neurotoxin. Whether or not MDMA is neurotoxic in humans is not known, but there is evidence that it is; for example, human MDMA users have lower concentrations of 5-HIAA in their cerebrospinal fluid (CSF) than controls. The difficulty in assessing the neurotoxic potential of MDMA in humans stems from the fact that there are no direct methods for evaluating the status of 5-HT neurons in the living human brain. Positron emission tomography (PET), when used in conjunction with a radioligand specific for the 5-HT neuron, is an imaging technique that could be used to study the status of 5-HT neurons in humans during life. Indeed, preliminary observations suggest that PET imaging with the 5-HT transporter ligand [11C]McN-5652 is useful for detecting brain 5-HT deficits in MDMA lesioned baboons. The overall goal of this project is to confirm this finding and extend it to humans. To achieve this goal, two series of studies are proposed, one in baboons and the other in humans. In preclinical studies, baboons will be lesioned with either MDMA or 2'-NH2-MTPT, an MPTP analog that, when administered with desmethylimipramine (DMI), is highly and selectively toxic to the brain 5-HT neurons. Baboons lesioned with MDMA, which is known to damage brain 5-HT systems in the entire forebrain will be used for "between subjects" comparisions and baboons lesioned with 2'-NH2-MPTP which will permit unilateral lesions of brain 5-HT systems will be used for "within subjects" comparisons. At 36 and 72 weeks after lesioning, tha animals will undergo PET studies with [11C]McN-5652 and lumbar punctures for CSF 5-HIAA detereminations. The animals will then be sacrificed for direct determination of tissue 5-HT axonal markers. These studies will offer the unique opportunity to study the relationship between alterations in specific [11C]McN-5652 binding measured in vivo by means of PET and changes in tissue 5-HT neuronal markers, i.e., 5-HT, 5-HIAA, {3H} citalopram binding sites, measured directly in postmortem tissue of the same animals.